# Sex hormone effects on neurodevelopment: Controlled puberty in transgender adolescents

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $707,054

## Abstract

Project Summary/Abstract
Sex represents a critical variable not only in typical neurodevelopment, but also neuropsychiatric disease.
Substantial sex differences have been identified in prevalence, course and outcome of psychiatric disorders,
with prior evidence indicating this occurs in a time-dependent fashion throughout the lifespan, with specific
epochs in early development and in the pubertal period. Despite clear epidemiological evidence for these
disparities, understanding of underlying biological mechanisms in humans is limited. Animal studies suggest a
critical role of sex hormones in both developmental periods, however translation of these mechanisms to
humans has been hampered by the lack of an experimental model that allows segregation of effects related to
early organizational effects and later activational processes in puberty. The recent advent of cross-sex
hormone therapy (CSHT) in adolescents with gender dysphoria, presents a unique opportunity to investigate
these processes, while also advancing the empirical basis of clinical care for this vulnerable population of
youth. While early data from comparable European clinics demonstrated that adolescents in late puberty
receiving GnRH treatment showed improved psychological functioning and unanimously opted to proceed with
CSHT in late adolescence, there is little to no empirical data guiding clinical practices of CSHT in early pubertal
adolescents, highlighting the need for further research to address the critical knowledge gap in this cohort of
youth. The research we propose has never been conducted in early pubertal adolescents, an important point
given the prevailing theoretical framework which posits that hormonal effects are exerted in defined, time-
sensitive developmental windows, with early and permanent organizational effects in the perinatal period, and
further activational changes occurring during adolescence. Studying an adolescent cohort is critical for this
population as it (1) establishes a neural basis for sex steroid influence in puberty as manifested in brain
anatomy and connectivity through a model of gender dysphoria and cross-sex hormone therapy, (2) identifies
independent processes by which estrogens and testosterone differentially affect individuals with a natal sex
background of either female- or male-typical early organizational effects and (3) maps these findings onto
behaviors that are most strongly associated with sexually dimorphic patterns of psychopathology in the
adolescent period. Results from this interdisciplinary proposal will provide a much-needed foundation for
understanding the longitudinal impact of treatments that are already being used in clinical settings and allow
better understanding of risk factors associated with disease that emerges along sex-specific trajectories from
the pubertal period, greatly improving clinical outcomes for both typically developing and GD youth.

## Key facts

- **NIH application ID:** 10479828
- **Project number:** 5R01MH115349-05
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** DAVID S HONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $707,054
- **Award type:** 5
- **Project period:** 2018-08-23 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10479828

## Citation

> US National Institutes of Health, RePORTER application 10479828, Sex hormone effects on neurodevelopment: Controlled puberty in transgender adolescents (5R01MH115349-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10479828. Licensed CC0.

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